AUTHOR=El Darazi Perla , El Khoury Léa , El Hage Krystel , Maroun Richard G. , Hobaika Zeina , Piquemal Jean-Philip , Gresh Nohad TITLE=Quantum-Chemistry Based Design of Halobenzene Derivatives With Augmented Affinities for the HIV-1 Viral G4/C16 Base-Pair JOURNAL=Frontiers in Chemistry VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.00440 DOI=10.3389/fchem.2020.00440 ISSN=2296-2646 ABSTRACT=

The HIV-1 integrase (IN) is a major target for the design of novel anti-HIV inhibitors. Among these, three inhibitors which embody a halobenzene ring derivative (HR) in their structures are presently used in clinics. High-resolution X-ray crystallography of the complexes of the IN-viral DNA transient complex bound to each of the three inhibitors showed in all cases the HR ring to interact within a confined zone of the viral DNA, limited to the highly conserved 5′CpA 3′/5′TpG 3′ step. The extension of its extracyclic CX bond is electron-depleted, owing to the existence of the “sigma-hole.” It interacts favorably with the electron-rich rings of base G4. We have sought to increase the affinity of HR derivatives for the G4/C16 base pair. We thus designed thirteen novel derivatives and computed their Quantum Chemistry (QC) intermolecular interaction energies (ΔE) with this base-pair. Most compounds had ΔE values significantly more favorable than those of the HR of the most potent halobenzene drug presently used in clinics, Dolutegravir. This should enable the improvement in a modular piece-wise fashion, the affinities of halogenated inhibitors for viral DNA (vDNA). In view of large scale polarizable molecular dynamics simulations on the entirety of the IN-vDNA-inhibitor complexes, validations of the SIBFA polarizable method are also reported, in which the evolution of each ΔE(SIBFA) contribution is compared to its QC counterpart along this series of derivatives.